47306-AC1
Diels-Alder Cycloaddition Reactions with Dihapto-Coordinated Pyridines
The constructions of numerous polyheterocyclic scaffolds has been achieved utilizing hetero Diels-Alder reactions. In particular, the isoquinuclidine skeleton, found in a variety of alkaloids (e.g., ibogaine) and their pharmaceutically-derived analogs, has been prepared using aza-butadienes, dihydropyridines, or pyridones, combined with various dienophiles. We reasoned that common pyridines would be attractive alternatives as sources of azadienes, but their aromatic stability normally renders them unsuitable for such cycloaddition reactions. Our research group has been exploring the effects of dihapto-coordination on the chemistry of aromatic molecules. Once coordinated, the aromatic ring is dearomatized, activating the aromatic toward new chemical transformations. We postulated that if 2,6-dimethoxypyridine (η2-DMP) were bound to {TpW(NO)(PMe3)}, the uncoordinated portion of this ring should take on a chemical nature similar to that of Danishefsky's diene. Specifically, the combination of π-donation from both tungsten and the methoxy groups was expected to render this pyridine a potent reagent for cycloaddition reactions. The initial goal of this PRF-funded study was to explore the potential of TpW(NO)(PMe3)(4,5-η2-DMP) as an azadiene synthon for azabicyclic frameworks. The DMP complex TpW(NO)(PMe3)(4,5-η2-DMP) (1) can be prepared by stirring a suspension of the benzene complex TpW(NO)(PMe3)(η2-benzene) and DMP in hexanes for 26 h. The resulting yellow precipitate is isolated in 79% yield as a 1:1 equilibrium mixture of coordination diastereomers. Once coordinated to tungsten, DMP was found to react with a broad range of alkene and alkyne dienophiles to form the isoquinuclidine core. The structural and stereochemical characterizations of the isolated products were assigned on the basis of CV, IR, 1H and 13C NMR, NOE and H-H coupling data and X-ray crystallography. Various one- and two-electron oxidants were screened with the expectation that a more electron-deficient tungsten (I) or tungsten (II) species would release the W-alkene bond in these complexes. Demetallation of the aza-bicyclooctadiene core was ultimately achieved in some cases by subjecting it to ceric ammonium nitrate (CAN). The activation of pyridine through dihapto coordination was first documented by our group using the examples of 2,6-lutidine and 2-(dimethylamino)pyridine. Other than this report, the only example that we are aware of involving cycloaddition to a pyridine are those of Gompper and Neunhoeffer who independently described the cycloaddition of dimethyl 2,6-bis(dimethyl-amino)pyridine-3,4- dicarboxylate and DMAD. However, in that case the aza-barralene readily rearomatized via a retrocycloaddition yielding a pentasubstituted benzene. Other relevant examples of pyridinium-like aromatic molecules undergoing cycloaddition include reactions with isoquinolinium and azoniaanthracene. The Diels-Alder reaction of an η2-benzene complex with N-methylmaleimide has also been demonstrated. Nitrile Metathesis. A Diels-Alder/retro Diels-Alder sequence was also proposed to prepare pyridines with novel substitution patterns. While unactivated nitriles have been observed to undergo Diels-Alder reactions only under harsh reaction conditions, Mander's reagent (ethyl cyanoformate) has been documented to undergo such a reaction with dienes at or below 20 °C. Hence, the DMP complex 1 was subjected to this reagent. While reaction of 1 and Mander's reagent gave a complex mixture of products, when the lutidine analog was exposed to ethyl cyanoformate at -10 °C, a single new η2-pyridine species was isolated in which one of the methyl groups has been replaced by an ester group, the product of a nitrile metathesis. Attempts to isolate the diazabicyclooctatriene intermediate were unsuccessful. In summary, the coordination of 2,6-dimethoxypyridine by {TpW(NO)(PMe3)} and subsequent removal of the metal provides the formal equivalent of a Diels-Alder cycloaddition with this heterocycle, a reaction that typically is thermodynamically unfavorable in absence of extreme pressures. Once formed the cycloadduct is moderately stable and in some cases can be isolated. The use of a dihapto-coordinated 2,6-dimethoxypyridine allows access to a full range of alkene and alkyne dienophiles, and in some cases, these azabicyclic skeletons can be chemically modified while bound to the tungsten fragment prior to their decomplexation. The results of this study have now been now been published in Organometallics. While the basic finding that dihapto-coordinated pyridines can undergo Diels-Alder reactions has important synthetic implications, the requirement of the pyridine to have substituents at the 2 and 6 positions to avoid nitrogen coordination presents a severe limitation for chemical synthesis. In year two, our research has refocused on methods for obtaining a dihapto-coordinated complex of pyridine itself. Using reversible nitrogen blocking strategies, we recently have achieved this goal, trapping the pyridine as its BH3 adduct, then replacing this protecting group with H+ to prevent N-coordination. We are now in the process of analyzing the chemical reactivity of this most unusual species.
